Solifenacin is a compound represented by Chemical Formula 1 below and is reported to have an excellent selective antagonistic action against muscarinic M3 receptors.

Meanwhile, although solifenacin or a pharmaceutically acceptable salt thereof may be stable in the state of a raw material, there is a problem with the drug in that it decomposes with time due to various factors involved in the process of manufacturing it into a final product. As a representative example, an amorphous form of solifenacin succinate is generated during the process of wet granulation and easily oxidized within a short period. In particular, the main degradation product (an oxidized form of solifenacin succinate) has been reported to be the major cause of the decomposition problems of the main drug. That is, it is difficult to develop a desirable formulation and process due to drug instability problems which may occur, depending on various process conditions such as reaction temperature, pH, reaction time, order of mixing, etc., or by interactions occurring when excipients, binders, lubricants, etc. are combined and come in contact with the active ingredient, depending on the characteristics of exipients, etc.
Additionally, the cohesiveness of solifenacin or a pharmaceutically acceptable salt thereof complicates the formulation process. KR Patent Application Publication No. 10-2007-0010132 discloses that it is preferred that any formulations containing solifenacin or a pharmaceutically acceptable salt thereof be manufactured via a wet granulation process because the content uniformity of solifenacin or a pharmaceutically acceptable salt thereof is difficult to ensure via direct compression and also they tend to adhere to the punch during the compression process.
Accordingly, commercial formulations on the market such as Vesicare® containing solifenacin succinate are manufactured via a wet granulation process, and various methods have been suggested to improve the stability of such formulations. For example, KR Patent Application Publication No. 10-2007-0010132 discloses, as a method of preventing the time-based decomposition of a drug in solifenacin succinate-containing formulation, a method of controlling the percentage of the amorphous form in the formulation to a certain amount or lower, thereby preventing the time-based decomposition, or controlling the water content contained in the formulation during manufacture, heat treatment and/or humidity treatment after manufacture, thereby lowering the content of the amorphous form. Additionally, the above KR Patent Application Publication No. 10-2007-0010132 discloses that, at the time of manufacturing a formulation containing solifenacin or its salt, the amorphization of solifenacin can be prevented by using a binder such as polyethylene glycol (PEG), thereby manufacturing a formulation capable of inhibiting the time-based decomposition.
Additionally, KR Patent Application Publication No. 10-2007-0098889 discloses that, in manufacturing a granular pharmaceutical composition containing solifenacin or a pharmaceutically acceptable salt thereof, the stability of the main component can be secured by using a binder having a Tg of 174° C. or below.
As described above, due to the strong cohesiveness of solifenacin or a pharmaceutically acceptable salt thereof as a raw material and its instability during the formulation process, it is very difficult to select a suitable formulation method. The previously-suggested methods may provide a certain degree of stability but the water content contained in the granules during the wet granulation process is affected by various conditions during the manufacturing process such as reaction time, order of mixing, etc., and thus controlling the percentage of the amorphous form to a certain amount or lower by adjusting the water content is very unlikely to improve the stability of the formulation when this method is applied to large-scale production.
Additionally, in the case of manufacturing a formulation via a wet granulation method, the main components generally tend to exhibit time-based decomposition due to their interaction with water or organic solvents such as alcohol, and due to heat treatment for the purpose of removing the solvents.
Additionally, there are also limitations in the methods of preventing the time-based decomposition of solifenacin via selection and utilization of a specific binder for the wet granulation method due to the instability of the wet method. In particular, polyethylene oxide, which was suggested as one of the binders, has incompatibility with a strong oxidant (Handbook of Pharmaceutical excipients, 4th edition), and in addition, when lactose or mannitol is mixed with polyethylene oxide, the release behavior of the drug may vary over the course of its storage life, and thus its incompatibility was disclosed by a publication released by DOW company during the CRS conference in 2008 (KR Patent Application Publication No. 10-2012-0093500). Accordingly, considering that polyethylene oxide limits the selectable scope of the main excipients, with the combined use of polyethylene oxide is not desirable.
Therefore, there is still a high demand for the development of a novel preparation capable of preventing the time-based decomposition of solifenacin or its salt while also providing easy control over the preparation process in a commercial production environment.